Prostate cancer is the most common solid tumor in American men (1). The wide spectrum of biologic behavior (2) exhibited by prostatic neoplasms poses a difficult problem in predicting the clinical course for the individual patient (3, 4). Public awareness of prostate specific antigen (PSA) screening efforts has led to an increased diagnosis of prostate cancer. The increased diagnosis and greater number of patients presenting with prostate cancer has resulted in wider use of radical prostatectomy for localized disease (5). Accompanying the rise in surgical intervention is the frustrating realization of the inability to predict organ-confined disease and clinical outcome for a given patient (5, 6). Traditional prognostic markers, such as grade, clinical stage, and pretreatment PSA have limited prognostic value for individual men. There is clearly a need to recognize and develop molecular and genetic biomarkers to improve prognostication and the management of patients with clinically localized prostate cancer. As with other common human neoplasia (7), the search for molecular and genetic biomarkers to better define the genesis and progression of prostate cancer is the key focus for cancer research investigations worldwide.
The new wave of research addressing molecular genetic alterations in prostate cancer is primarily due to increased awareness of this disease and the development of newer molecular technologies. The search for the precursor of prostatic adenocarcinoma has focused largely on the spectrum of microscopic changes referred to as “prostatic intraepithelial neoplasia” (PIN). Bostwick defines this spectrum as a histopathologic continuum that culminates in high grade PIN and early invasive cancer (8). The morphologic and molecular changes include the progressive disruption of the basal cell-layer, changes in the expression of differentiation markers of the prostatic secretory epithelial cells, nuclear and nucleolar abnormalities, increased cell proliferation, DNA content alterations, and chromosomal and allelic losses (8, 9). These molecular and genetic biomarkers, particularly their progressive gain or loss, can be followed to trace the etiology of prostate carcinogenesis. Foremost among these biomarkers would be the molecular and genetic markers associated with histological phenotypes in transition between normal prostatic epithelium and cancer. Most studies so far seem to agree that PIN and prostatic adenocarcinoma cells have a lot in common with each other. The invasive carcinoma more often reflects a magnification of some of the events already manifest in PIN.
Early detection of prostate cancer is possible today because of the widely propagated and recommended blood PSA test that provides a warning signal for prostate cancer if high levels of serum PSA are detected. However, when used alone, PSA is not sufficiently sensitive or specific to be considered an ideal tool for the early detection or staging of prostate cancer (10). Combining PSA levels with clinical staging and Gleason scores is more predictive of the pathological stage of localized prostate cancer (11). In addition, new molecular techniques are being used for improved molecular staging of prostate cancer (12, 13). For instance, reverse transcriptase-polymerase chain reaction (RT-PCR) can measure PSA of circulating prostate cells in blood and bone marrow of prostate cancer patients.
Despite new molecular techniques, however, as many as 25 percent of men with prostate cancer will have normal PSA levels—usually defined as those equal to or below 4 nanograms per milliliter of blood (14). In addition, more than 50 percent of the men with higher PSA levels are actually cancer free (14). Thus, PSA is not an ideal screening tool for prostate cancer. More reliable tumor-specific biomarkers are needed that can distinguish between normal and hyperplastic epithelium, and the preneoplastic and neoplastic stages of prostate cancer.
Identification and characterization of genetic alterations defining prostate cancer onset and progression is important in understanding the biology and clinical course of the disease. The currently available TNM staging system assigns the original primary tumor (T) to one of four stages (14). The first stage, T1, indicates that the tumor is microscopic and cannot be felt on rectal examination. T2 refers to tumors that are palpable but fully contained within the prostate gland. A T3 designation indicates the cancer has spread beyond the prostate into surrounding connective tissue or has invaded the neighboring seminal vesicles. T4 cancer has spread even further. The TNM staging system also assesses whether the cancer has metastasized to the pelvic lymph nodes (N) or beyond (M). Metastatic tumors result when cancer cells break away from the original tumor, circulate through the blood or lymph, and proliferate at distant sites in the body.
Recent studies of metastatic prostate cancer have shown a significant heterogeneity of allelic losses of different chromosome regions between multiple cancer foci (21-23). These studies have also documented that the metastatic lesion can arise from cancer foci other than dominant tumors (22). Therefore, it is critical to understand the molecular changes which define the prostate cancer metastasis especially when prostate cancer is increasingly detected in early stages (15-21).
Moreover, the multifocal nature of prostate cancer needs to be considered (22-23) when analyzing biomarkers that may have potential to predict tumor progression or metastasis. Approximately 50-60% of patients treated with radical prostatectomy for localized prostate carcinomas are found to have microscopic disease that is not organ confined, and a significant portion of these patients relapse (24). Utilizing biostatistical modeling of traditional and genetic biomarkers such as p53 and bcl-2, Bauer et al. (25-26) were able to identify patients at risk of cancer recurrence after surgery. Thus, there is clearly a need to develop biomarkers defining various stages of the prostate cancer progression.
Another significant aspect of prostate cancer is the key role that androgens play in the development of both the normal prostate and prostate cancer. Androgen ablation, also referred to as “hormonal therapy,” is a common treatment for prostate cancer, particularly in patients with metastatic disease (14). Hormonal therapy aims to inhibit the body from making androgens or to block the activity of androgen. One way to block androgen activity involves blocking the androgen receptor; however, that blockage is often only successful initially. For example, 70-80% of patients with advanced disease exhibit an initial subjective response to hormonal therapy, but most tumors progress to an androgen-independent state within two years (16). One mechanism proposed for the progression to an androgen-independent state involves constitutive activation of the androgen signaling pathway, which could arise from structural changes in the androgen receptor protein (16).
As indicated above, the genesis and progression of cancer cells involve multiple genetic alterations as well as a complex interaction of several gene products. Thus, various strategies are required to fully understand the molecular genetic alterations in a specific type of cancer. In the past, most molecular biology studies had focused on mutations of cellular proto-oncogenes and tumor suppressor genes (TSGs) associated with prostate cancer (7). Recently, however, there has been an increasing shift toward the analysis of “expression genetics” in human cancer (27-31), i.e., the under-expression or over-expression of cancer-specific genes. This shift addresses limitations of the previous approaches including: 1) labor intensive technology involved in identifying mutated genes that are associated with human cancer; 2) the limitations of experimental models with a bias toward identification of only certain classes of genes, e.g., identification of mutant ras genes by transfection of human tumor DNAs utilizing NIH3T3 cells; and 3) the recognition that the human cancer associated genes identified so far do not account for the diversity of cancer phenotypes.
A number of studies are now addressing the alterations of prostate cancer-associated gene expression in patient specimens (32-36). It is inevitable that more reports on these lines are to follow.
Thus, despite the growing body of knowledge regarding prostate cancer, there is still a need in the art to uncover the identity and function of the genes involved in prostate cancer pathogenesis. There is also a need for reagents and assays to accurately detect cancerous cells, to define various stages of prostate cancer progression, to identify and characterize genetic alterations defining prostate cancer onset and progression, to detect micro-metastasis of prostate cancer, and to treat and prevent prostate cancer.